Preparation of pyrimidine derivatives by ether cleavage



United States Patent ()fitice 3,161,642 Patented Dec. 15, 1964 3,161,642 PREPARATIGN F PYREMIDINE DERIVATIVES BY ETHER CLEAVAGE Roger J. Tull, Metuchen, and Edward W. Tristram, Cranford, N1, assignors to Merck dz o., Inc Rahway, N..l., a corporation of New Jersey N0 Drawing. Filed May 10, 1963, Ser. No. 279,613 (Zlaims. (Cl. 26-256.4)

This application is a continuation-in-part of our application Serial No. 854,274, filed November 20, 1959, and now abandoned.

This invention relates generally to a method for making quaternary salts. More particularly, it is concerned with a process of making l-pyrimidylmethyl pyridinium salts directly from a pyrimidylmethyl ether. Still more particularly, it is concerned With a synthesis of 1-(2- loweralkyl-4-amino-5-pyrimidylmethyl)-alkyl pyridinium chlorides by reaction of a 2-loweralky1-4-amino-S-hydrocarbonoxymethyl pyrimidine with an alkyl pyridinium chloride.

Quaternary salts having the general Formula I hereinbelow are useful in the treatment of coccidiosis, a common and widespread poultry disease. When used for this purpose, such compounds are administered to the animals by way of the feed and are effective in preventing coccidiosis when administered at levels of from about 0.0005 to about 0.05% by Weight of the total feed consumed, the amount required for optimum prevention or control of the disease varying with the particular compound employed.

NH JEX In the above formula, R and R are lower alkyl groups, n is a whole integer having a value of l or 2, and X represents halogen.

The methods heretofore known for preparing such quaternary salts from a 2-loweralkyl-4-amino-S-hydrocarbonoxymethyl pyrimidine required the cleavage of the pyrimidine ether to a 2-loweralkyl-4-amino-S-halomethyl pyrimidine, such as a S-bromomethyl pyrimidine, recovery of said pyrimidine and formation of the quaternary compound in a separate step by condensation with the appropriate alkyl pyridine base. Although cleavage of the pyrimidine ethers to the corresponding halomethyl pyrimidine with certain mineral acids is known, these known processes require the use of difficult and unwieldy reaction conditions, expensive reagents and/or excessive quantities of reagents. Furthermore, in these previously available syntheses, recovery of the S-halomethyl pyrimidine is necessary with the result that a second distinct reaction is required to make the quaternary sal t s described above. It has further been reported that vitamin B may be prepared by reacting together 4-methyl-5-(p hydroXyethyD-thiazole hydrochloride and 2-methyl-4- amino-S-methoxymethyl pyrimidine hydrochloride, but the yield of vitamin B thus obtained is unsatisfactory and the reaction conditions employed are unsuitable.

In accordance with the present invention, a method has now been discovered for obviating these diificulties and producing the quaternary salts of Formula I (where X is chloride) directly and in high yield from a pyrimidylmethyl ether without having first to prepare and isolate a S-halomethyl pyrimidine. An object of the invention is, therefore, to provide a practical, technically ,feasible method for converting a 5-pyrimidylmethyl ether directly in one step to a l-(pyrimidylmethyD-alkyl pyridinium chloride. A further object is provision of such a method whereby the desired quaternary salt is produced in good yield. Still another object is a synthesis which is carried out at atmospheric pressure and without the need for expensive or excessive quantities of reagents. A more particular object is provision of a synthesis of l-(2-loweralkyl-4-amino-5-pyrimidylmethyl)-alkyl pyridinium quaternary chlorides from a 2-loweralkyl-4-amino-5-hydrocarbonoxymethyl pyrimidine and an appropriate alkyl pyridine. An additional object is provision of a method by which the quaternary salt is obtained directly in good yield without the need for isolating any intermediate products. Still other objects will become apparent from the detailed discussion of our invention set forth below.

We have discovered that l-(2-loWeralkyl-4-amino-5- pyrimidylmethyl)-alkyl pyridinium quaternary chlorides having the general Formula I below may be obtained directly in good yield by reacting together under the proper conditions 2-loweralkyl 4-amino-5-hydrocarbonoxymethyl pyrimidine hydrochloride (II) and an alkyl pyridine hydrochloride (III), a process which may be represented structurally as:

where R and R are lower alkyl radicals, R is an alkyl or aralkyl radical having less than nine carbon atoms, and ri has a value of l or 2. When n is 2, the alkyl groups attached to the pyridine ring may be the same or diiferent, although only one of the alkyl groups may be alpha to the nitrogen atom. R and R may also, of course, be the same or diiferent.

The pyrimidine reactant employed as one of the starting materials in the process of our invention is a hydrochloride salt of a 2-loweralkyl-4-amino-5hydrocarbonoxymcthyl pyrimidine. The hydrocarbon radical which forms part of the ether substituent at the 5 position (R of Formula II) may be an alkyl or an aralkyl radical, and preferably is a radical containing less than nine carbon atoms. Thus, R may be a lower alkyl group such as a methyl, ethyl, isopropyl, propyl, t-butyl or amyl group, or an aralkyl group such as the benzyl radical. Pyrimidines having a methoxymethyl or isopropoxymethyl substituent at the 5 position have been found to be very satisfactory in our process.

A lower alkyl group is also present at the 2 position of the pyrimidine ring, and examples of such groups that might be mentioned are methyl, ethyl, propyl, isopropyl, butyl and amyl radicals. We prefer alkyl radicals having less than about seven carbon atoms. It will be appreciated, therefore, that a number of substituted pyrimidines may be used satisfactorily in synthesizing the quaternary salts described herein. Representative examples of this group of starting materials are 2-methyl-4-amino-5-methoxymethyl pyrimidine, 2-1nethyl-4-amino-5-amyloxymethyl pyrimidine, 2-methyl-4-amino-5-ethoxymethyl pyrimidine, 2-propyl-4-amino-S-methoxymethyl pyrimidine, Z-propyl-4-amino-5-butoxymethyl pyrimidine, 2-propyl-4-amino-S-ethoxymethyl pyrimidine, 2-ethy1-4-amino-5-ethoxymethyl pyrimidine, 2-amyl-4-amino-S-benzyloxymethyl pyrimidine, and 2-isopropyl-4-amino-5-t-butoxymethyl pyrimidine.

Most of these 2-loweraikyl-4-amino-5-hydrocarbonoxymethyl pyrimidines are known compounds. Those which have not been specifically disclosed in the literature are readily prepared by the methods utilized for the known related compounds. For example, the pyrimidine reactants described above may be synthesized following the procedures set forth in Cline et al., J. Am. Chem. Soc. 59 1052 (1947) or US. Patent No. 2,350,265.

According to the present invention, these pyrimidylmethyl ethers are reacted with an alkylpyridiue hydrochloride under the conditions described below to produce directly a l-pyrimidylmethyl alkyl pyridinium chloride. As the alkyl pyridine reactant, we employ a hydrochloride salt of compounds such as Z-methyl pyridine, 4- methyl pyridine, Z-methyl-S-ethyl pyridine, 3-methyl pyridine, 2,4-dimetl1yl pyridine, 4-propyl pyridine, 4-ethylpyridine, Z-ethyl pyridine, 2,3-diethyl pyridine, 2,4-diethyl pyridine, 4-t-butyl pyridine, and the like. The pyridine nucleus may be substituted with one or two lower alkyl radicals, although these radicals need not be the same. When there are two such alkyl groups present, it is necessary that only one of them be in the alpha position with respect to the pyridine nitrogen atom since production of the desired quaternary salt is not satisfactory under the reaction conditions described when both of the alpha carbons are alkylated.

In our process we employ a molar excess of the alkyl pyridine reactant over the pyrimidine reactant. We have found that satisfactory results are obtained when from about 1.5 to 10 moles of alkyl pyridine compound are used per mole of pyrimidine, although larger quantities of the alkyl pyridine may be employed without affecting the reaction adversely. We prefer to use from about 1.75 to about 6 moles of alkyl pyridine per mole of pyrimidine, and optimum results are achieved with an alkyl pyridinezpyrimidine molar ratio of about 2-4-11, these molar quantities being expressed in terms of the free bases.

As will be noted from the above flow diagram, in our process a pyrimidylmethyl ether (II) is cleaved by the alkylpyridine hydrochloride with formation of the desired quaternary salt. Although the two reactants may be mixed as hydrochloride salts and the reaction carried out as described hereinbelow, it is more convenient and is preferred to charge the pyrimidine and alkylpyridine compounds to the reaction mixture as free bases, and to form the salts in situ by addition of hydrogen chloride to the reaction mixture. The salts form very promptly with evolution of heat.

One feature of our process is that the cleavage of the 2 loweralkyl 4 amino hydrocarbonoxymethyl pyrimidine with the alkylpyridine hydrochloride is brought about in the presence of excess hydrogen chloride, i.e. an excess over the amount required to convert all of the pyrimidine and alkylpyridine base present to the corresponding hydrochlorides. We employ a 7.5100% excess of acid (over the amount required for salt formation), and prefer to use about a 10-75% excess.

The process is carried out at atmospheric pressure and at elevated temperatures of between about 110 and 200 C. Temperatures of from about 120 C. to about 165 C. are particularly preferred in our process. It will be appreciated that the optimum reaction time is dependent to a large degree on the temperature employed. Satisfactory results are obtained in as little as 5 to 10 minutes at higher temperatures whereas 1012 hours or longer may be required at the lower temperatures. When the process is conducted within the preferred temperature range, the quaternary salt is formed in high yield in from about 1 to 8 hours. The reaction mixture is a heterogenous one at several stages of the process so that the efiieiency of mixing may become a factor in large-size equipment, and the optimum reaction time will increase as stirring eificiency decreases.

The direct quaternization of this invention is carried out in an organic solvent medium. A number of arcmatic and aliphatic solvents can be employed, representative examples of which are toluene, xylene, secondary butyl benzene, tetrachloroethane, tetrachloroethylene and the chlorobenzenes. It is convenient to use a solvent having a boiling point close to the desired reaction temperature so that the process may be conducted under reflux. The solvent should, of course, have a boiling point of at least 110 C. in order to satisfy the temperature conditions discussed above. In addition, the solvent should be water-immiscible for the reason that undesired reaction by-products such as lower alkanols and/ or water should be continuously removed from the reaction site in order to achieve optimum yields, and this cannot be effectively accomplished when a water-miscible solvent is used as the reaction medium. If these by-products are not so removed, the yield of desired quaternary salt is significantly decreased. Several methods or techniques are suitable for removal of low-boiling by-products, such as continuous distiliation of the organic solvent and replacement thereof by fresh solvent, distillation or refluxing through a steam-cooled condenser which permits escape of low-boiling material but returns the organic solvent to the reaction vessel, or use of connnercially-available mechanical separators.

At the end of the reaction period, the quaternary salt is conveniently recovered by cooling the reaction medium and separating the substantially pure solid quaternary salt from the organic solvent. The product is freed of residual reaction solvent by washing with suitable soivents such as acetonitrile, isopropanol or ether. When the direct quaternization process of this invention is carried out under the previously described reaction conditions, the desired l-(2-loweralkyl-4-amino-5-pyrimidylmethyl)-alkyl pyridinium chloride hydrochlorides are obtained in yields exceeding and in many cases the yields will approach of theoretical.

l-pyrimidylmethyl alkyl pyridinium chlorides representative of those which may be synthesized by the novel process described hereinabove include:

1- (2-ethyl-4-amino-S-pyrimidylmethyl -2-methyl-pyridinium chloride hydrochloride 1-(2-n-propyl-4-amino-5-pyrimidylmethyl) -2-methyl pyridinium chloride hydrochloride l-(2-rnethyl-4-amino-5pyrimidylmethyl)-2-methyl pyridinium chloride hydrochloride 1-(2-n-propyl-4-amino-5-pyrimidylmethyl)-4-methyl pyridinium chloride hydrochloride l-(2-ethyl-4-amino-5pyrimidylmethyl)-4-methyl pyridinium chloride hydrochloride 1-(2-methyl-4-amino-5-pyrimidylmethyl) -4-ethyl pyridinium chloride hydrochloride 1- (2-metl1yl-4-amino-5-pyrimidylmethyl -2,4-dimethyl pyridinium chloride hydrochloride 1- 2-methyl-4-amino-5-pyrimidylmethyl -2-methyl-5- ethyl pyridinium chloride hydrochloride 1- (2-propyl-4-amino-S-pyrirnidylmethyl -2-methyl-5- ethyl pyridinium chloride hydrochloride 1-(2-ethyl-4-amino-5-pyrimidylmethyl)-2,3-dimethyl pyridinium chloride hydrochloride 1- (Z-ethyl-4-amino-5-pyrimidylmethyl) -2-methyl-5-ethyl pyridinium chloride hydrochloride 1- (2-amyl-4-amino-5-pyrimidylmethyl) -2-methyl pyridinium chloride hydrochloride The following examples are given for the purpose of illustration and not by way of limitation:

EXAMPLE 1 1 (Z-n-Propy l-4-A mine-5 -Pyrimidylmethyl -2-M ethyl Pyridinium Chloride Hydrochloride A. 5 g. of '2-propyl-4-amino-5-methoxymethyl pyrimidine (0.0275 mole), ml. of Z-methyl pyridine (0.101 mole) and 50 ml. of xylene are placed in a 250 ml. flask equipped with reflux condenser, stirrer, thermometer and gas inlet tube. Hydrogen chloride gas is added to this mixture at a rate of 0.32 g. per minute for 23 minutes (0.2 mole). The temperature rises to about 67 C. The gas inlet tube is replaced with a distillation unit and the mixture heated at the reflux temperature (138 C.) for 2 hours during which time fresh xylene is added to replace the volume of liquid that distils. An additional 10 ml. of '2-methyl pyridine is added and the mixture refluxed for 40 minutes. At the end of the reflux period, the reaction mixture is cooled to 65 C., the xylene decanted and 25 ml. of acetonitrile added to the residue. The resulting mixture is stirred at room temperature for about 12 hours, filtered and the solid 1 (2 n propyl 4 amino 5 pyrimidylmethyl)-2-methyl pyridinium chloride hydrochloride thus obtained Washed with 10 ml. of acetonitrile and two 10-ml. portions of ether. 7.93 g. of product (91.2%) are obtained, M.P. 246-247" C.

When the above reaction is carried out using chlorobeuzene as the reaction solvent instead of xylene and omitting the second addition of 2-methy1 pyridine, the quaternary salt is obtained in approximately 86% yield. B. 25 g. of 2-n-p-ropyl-4-amino-5-methoxymethyl pyrimidine and 34 ml. of 2-methyl pyridine are dissolved in 125 ml. of xylene and g. of gaseous hydrogen chloride is added over the course of 20 minutes. The temperature rises to about 80? C. The reaction flask is fitted with a steam-heated condenser and the mixture is refluxed with stirring for 2 hours. The reaction mixture is then cooled, the xylene decanted, and the semisolid residue stirred With 125 m1. of isopropyl alcohol. The product is filtered, washed with 50 ml. of isopropyl alcohol and then with 50 ml. of acetone and dried under vacuum. 37 g. (85%) of l-(2 n-propy1-4-amino-5-pyrimidylmethyl)-2-methyl pyridinium chloride hydrochloride is obtained.

When the experiment of Example 1B is carried out employing a 5 /2 hour reflux period instead of the -2 hours used in Example 13, the 1-(2-n-propy1-4-amino-5- pyrimidylmethyl)-2-methy1 pyridinium chloride hydrochloride is obtained in 89% yield.

EXAMPLE 2 1-(2-n-Pr0pyl-4-Amin0-5-Pyrimidylmethyl)-2-Methyl Pyridinium Chloride Hydrochloride 5 g. of 2-n-propyl-4-amino-5-methoxymethyl pyrimidine (0.0275 mole) and 10 ml. of Z-methyl pyridine (0.101 mole) are added to a flask equipped with stirrer, thermometer, reflux condenser and gas inlet tube. 7.3 g. (0.2 mole) of hydrogen chloride gas is introduced to this mixture at a rate of 1116 g. per minute. After the initial exothermic reaction subsides, the gas inlet tube is replaced with a steam-heated condenser and the mixture heated at about 138 C. for one hour. It is then placed under vacuum for an additional hour, then cooled to about 40 C. and slurried with ml. of acetonitrile. The slurry is stirred at room temperature for 2 hours'and the solid 1-(2-n-propyl-4-amino-5-pyrimidylmethyl)-2- methyl pyridinium chloride hydrochloride isolated by filtration, Washed with acetonitrile and ether and dried. 5.11 g. of quaternary salt, M.P. 244-245 C., are obtained.

6 EXAMPLE 3 1 (2-n-Pr0pyl-4-A mine-5 -Pyrimidylmethyl -2-M ethyl Pyridinium Chloride Hydrochloride When the procedure of Example 1B is carried out employing 50 ml. of secondary butyl benzene as solvent in place of xylene, and refluxing the reaction mixture for 20 minutes at 168 C. after hydrogen chloride addition is complete, 5.2 g. of l-(2-n-propyl-4-amin0-5-pyrimidylmethyl)-2-methyl pyridinium chloride hydrochloride, M.P. 246-248 C., are obtained.

EXAMPLE 4 1-(2-Ethyl-4-Amino-S-Pyrimidylmezhyl)-2-Methyl Pyridinium Chloride Hydrochloride One mole (167 g.) of 2-ethyl-4-amino-S-methoxymethyl pyrimidine and two moles (200 ml.) of 2-methyl pyridine are mixed in a round-bottom one liter three-neck flask. Hydrogen chloride is introduced, with cooling, at 60 to 70 C. until an exotherm is no longer detectable. The amount of hydrogen chloride absorbed is about 130 g. (3.6 moles). The agitated mixture is heated for 3 hours at about 150 C. A small amount of liquid distills during the heating. Upon cooling to 50 C., 500 ml. of acetonitrile is added to disperse the thick melt. The contents of the flask are transferred to a larger vessel, further diluted with one liter of acetonitrile, agitated for 1 hour and filtered. The solid 1-(2-ethyl-4-amino-S-pyrimidylmethyl)-2-methyl pyridinium chloride hydrochloride is washed With two IOO-ml. portions of acetonitrile, two ml. portions of acetone and dried overnight at 70 C.

EXAMPLE 5 1-(2-n-Pr0pyl-4-Amin0-5-Pyrimidylmethyl)-4-Methyl Pyridinium Chloride Hydrochloride 25 g. of 2-n-propyl-4-amino-S-methoxymethyl pyrimidine and 50 ml. of 4-methyl pyridine in 250 ml. of xylene is treated with 36.5 g. of hydrogen chloride gas. As the temperature rises during the introduction of hydrogen chloride, two clear liquid phases are formed. The reaction mixture is refiuxed using a condenser heated with steam. After refluxing for 2 hours the mixture is cooled, the xylene is decanted and the solid residue is stirred for about 15 hours with 250 ml. of acetonitrile. The 1-(2- n-propyl 4-amino-S-pyrimidylmethyl)-4-rnethyl pyridinium chloride hydrochloride is filtered, washed with acetonitrile and with acetone, and dried under vacuum.

When the above reaction is carried out with Z-methyl- 4-amino-5-methoxymethyl pyrimidine, 1-(2-methyl-4- amino-S-pyrimidylmethyl)-4-methyl pyridinium chloride hydrochloride is obtained.

When the above reaction is carried out with 2-ethyl-4- amino-S-methoxymethyl pyrimidine, 1-(2-ethyl-4-amino- S-pyrimidylmethyl)-4-methyl pyridinium chloride hydrochloride is obtained.

EXAMPLE 6 1-(2-n-Pr0pyl-4-Amino-S-Pyrimidylmethyl)-2-Methyl Pyridinium Chloride Hydrochloride A xylene solution of 28.9 g. (0.16 m.) of 2-propyl-4- amino-5-methoxymethyl pyrimidine in ml. of xylene is mixed with 39 ml. (0.4 m.) of 2-methyl pyridine in a 500 ml. flask fitted with an agitator, steam-heated riser and water cooled condenser. 23.2 g. (0.635 m.) of anhydrous hydrogen chloride is added to the xylene mixture while the temperature of the mixture is maintained at about 50 C., with cooling. The reaction mixture is then heated to reflux and maintained at this temperature for 5 /2 hours. The volume of the reaction mixture is maintained constant by addition of fresh xylene. At the end of the reaction period the mixture is cooled and the remaining xylene decanted. The 1-(2-n-propyl-4-amino- S-pyrimidylmethyi)-2-methyl pyridinium chloride hydrochloride is recovered from the residue remaining in the 6 reaction flask by the procedure of Example 1B. There is obtained 41.2 g. of quaternary salt (82% yield).

EXAMPLE 7 1 (2-Elhyl-4-A min-5 -Pyrimidylmethyl -2-M ethyl Pyridinium Chloride Hydrochloride 5.0 g. of 2-ethyl-4-amino-5-isopropoxymethyl pyrimidine and 5.0 ml. of Z-methyl pyridine in 50 ml. of chlorobenzene is saturated with gaseous hydrogen chloride. The solids initially formed gradually melt as the temperature rises. After heating at reflux for 1 /2 hours the reaction mixture is cooled, the chlorobenzene decanted, and the semi-solid product treated with 50 ml. of acetonitrile. After stirring for 1 hour at room temperature, the 1-(2-ethyl-4-amino-S-pyrimidylrnethyl)-2-methyl pyridinium chloride hydrochloride is filtered, Washed with acetonitrile and then with acetone, and air-dried at 50 C. to give 3.9 g. of product, MP. 244247 C.

EXAMPLE 8 1-(2-Ethyl-4-Amino-S-Pyrimidylmethyl) -2-Methyl-5- Ethyl Pyridinium Chloride Hydrochioride 25 g. of 2-ethyl-4-amino-S-methoxymethyl pyrimidine and 44 ml. of Z-methyl-S-ethyl pyridine are dissolved in 250 ml. of xylene, and 20 g. of gaseous hydrogen chloride is added over the course of 20 minutes. Xylene is slowly distilled from the reaction mixture for 2 hours, fresh xylene being added to keep the volume of the reaction mixture constant. The mixture is then cooled, the xylene decanted, and the residue stirred with 125 ml. of acetonitrile for 15 hours. The resulting solid 1-(2-ethyl- 4-amino-S-pyrimidylmethyl)-2-niethyl-5-ethyl pyridinium chloride hydrochloride is recovered by filtration and washed with acetonitrile and dried under vacuum.

Any departure from the above description which conforms to the present invention is intended to be included within the scope of the claims.

We claim:

1. The process for preparing 1-(2-propyl-4-amino-5- pyrimidylmethyl)-2-methyl pyridinium chloride hydrochloride that comprises heating together in a xylene medium 2-propyl-4-amino-5-methoxymethyl pyrimidine hydrochloride and Z-methyl pyridine hydrochloride in the presence of hydrochloric acid, wherein the reaction is carried out at atmospheric pressure and at substantially the reflux temperature of xylene, and wherein the amount of hydrochloric acid present is from about 10-75% in excess of that required for formation of said pyrimidine and said Z-methyl pyridine hydrochlorides, and continuously renoving from the reaction medium substances that are insoluble in xylene and that have a boiling point of less than the reflux temperature of xylene.

2. The process for preparing 1-(2-propyl-4-amino-5-py rimidylmethyD-4-methyl pyridinium chloride hydrochloride that comprises heating together in a xylene medium 2-propyl-4-aminc-S-methoxyrnethyl pyrin idine hydrochloride and 4-methyl pyridine hydrochlorice in the presence of hydrochloric acid, wherein the reaction is carried out at atmospheric pressure and at substantially the reflux temperature or" xylene, and wherein the amount of hydrochloric acid present is from about 1075% in excess of that required for formation of said pyrimidine and said 4-methyl pyridine hydrochlorides, and continuously removing from the reaction medium substances that are insoluble in Xylene and that have a boiling point of less than the reflux temperature of xylene.

3. The process for preparing 1-(2-propyl-4-amino-5-pyrimidylmethyl)-2-methyl pyridiniurn chloride hydrochloride that comprises heating together at about 110200 C. 2-propyl-4-amino-5-methoxyrnethyl pyrimidine hydrochloride and 2-methyl pyridine hydrochloride in the presence of hydrochloric acid, wherein the reaction is carried out at atmospheric pressure and in a water-immiscible organic solvent having a boiling point of between 110- 200 C., and wherein the amount of hydrochloric acid present is from about 7.5% in excess of that required for formation of said pyrimidine and said Z-rnethyl pyridine hydrochlorides, and continuously removing from the reaction medium substances that are insoluble in the reaction solvent and that have a boiling point of less than C.

4. The process for preparing 1-(2-propy1-4-amino-5-pyrirnidylmethyl)-4-methy1 pyridinium chloride hydrochloride that comprises heating together at about 110200 C. 2-propy1-4-amino-S-methoxymethyl pyrimidine hydrochloride and 4-methyi pyridine hydrochloride in the presence of hydrochloric acid, wherein the reaction is carried out at atmospheric pressure and in a water-immiscible organic solvent having a boiling point of between 110- 200 C., and wherein the amount of hydrochloric acid present is from about 7.5100% in excess of that required for formation of said pyrimidine and said 4-methyl pyridine hydrochlorides, and continuously removing from the reaction medium substances that are insoluble in the reaction solvent and that have a boiling point of less than 110 C.

5. The process for preparing 1-(2-loweralkyl-4-amino-5- pyrimidylmethyl)-loweralkyl pyridinium chloride hydrochloride of the formula 0015? 3 (ll-.HCl

and an alkyl pyridine hydrochloride of the formula M wherein the reaction is carried out at atmospheric pressure and in a water-immiscible organic solvent having a boiling point of between 110200 C., and wherein the amount of hydrochloric acid present is from about 7.5-100% in excess of that required for formation of said pyrimidine and said alkyl pyridine hydrochlorides, and continuously removing from the reaction medium substances that are insoluble in the reaction solvent and that have a boiling point of less than 110 C., wherein in the above formulas R and R are loweralkyl radicals, R is selected from the class consisting of alkyl and aralkyl radicals having less than 9'carbon atoms and n is a positive interger of less than 3 and where only one of the alpha carbon atoms of the pyridine is alkylated when n is 2.

References Cited by the Examiner UNITED STATES PATENTS 2,235,862 3/41 Zirna 260-2566 2,328,595 9/43 Williams et a1 260-2566 OTHER REFERENCES Dornow et al.: Ber. Deut. Chem, vol. 80, pages 502- 509.

TRVING MARCUS, Primary Examiner.

NICHOLAS S. RlZZO, Examiner. 

5. THE PROCESS FOR PREPARING 1,(2-LOWERALKYL-4-AMINO-5PYRIMIDYLMETHYL)-LOWERALKYL PYRIDINIUM CHLORIDE HYDROCHLORIDE OF THE FORMULA 